Blood-Based Biomarkers in Parkinson’s
Monday, 14th September 2020

Recently, a team at Lund University published results in JAMA on a potential blood test for Alzheimer’s. It measures levels of plasma phospho-tau217 (P-tau217), a protein present in the brains of people with Alzheimer’s and some other neurodegenerative disorders. Though more research is needed to validate this test, it is positive news for Alzheimer’s and related diseases like Parkinson’s.

Because neurodegenerative diseases share some underlying pathology — and have similar challenges in biomarker development — a breakthrough in one can lead to progress in others. An example of this is the A/T/N classification framework for Alzheimer’s disease biomarkers, published in Neurology in 2016. In the framework, “A” is for amyloid-beta, “T” for tau, and “N” for neurodegeneration or neuronal injury, three pathological features of Alzheimer’s the paper’s authors put forth as essential biomarker categories for research.

The authors asserted that a system of biomarkers, rather than one alone, was necessary because Alzheimer’s is a complex disease and changes over time. Doctors and researchers need biomarkers that can help differentiate Alzheimer’s patients across the entire spectrum of disease, from its earliest stages before symptoms develop through severe dementia. The same is true in Parkinson’s, a highly heterogeneous disease that changes over time. One biomarker is probably not going to be enough to diagnose or track Parkinson’s disease progression. We suspect we will leverage a similar approach, using multiple biomarkers in combination. The elements of the system will be different — it is possible we will use biomarkers for alpha-synuclein instead of amyloid-beta, for example — but here again we can build on progress in Alzheimer’s.

Neurofilament light(NfL)has emerged as a blood-based biomarker of neurodegeneration in Alzheimer’s and recent evidence points to its utility in Parkinson’s. Results from a study published a few weeks ago in Movement Disorders by Brit Mollenhauer, MD, Danielle Graham, PhD, and others found that in people with Parkinson’s, NfL is significantly higher than in those without and that it continues to go up over time. In the study, which used sample from The Michael J. Fox Foundation’s Parkinson’s Progression Markers Initiative (PPMI), the researchers saw a correlation between increases in Movement Disorder Society (MDS)–UPDRS III and serum NfL levels.

This finding makes NfL the first biomarker of Parkinson’s progression.

Neurofilament light is not specific for Parkinson’s since it’s a general marker of neurodegeneration, but it’s a start. The next step is to determine the other pieces of the puzzle. What additional biomarkers do we need to be looking at to develop a comprehensive picture of Parkinson’s? It is possible that tau will be among them. Another PPMI study published this summer in Annals of Neurology tested three Alzheimer’s disease cerebrospinal fluid biomarkers (beta-amyloid, total tau, and phosphorylated tau) in people with early Parkinson’s disease over several years as potential predictors of clinical decline. Data suggests all three may have prognostic value in early Parkinson’s, as they deviated modestly from controls over time. We haven’t yet looked at P-tau217 in Parkinson’s, which was the form used in the Alzheimer’s blood test, but it is important to consider it based on these exciting results.

The Michael J. Fox Foundation has developed cohorts and biospecimen collections to conduct this research, as have other groups. You can test a hypothesis in smaller cohorts — the NfL investigators began in the 24-Hour Biofluid Sampling and De Novo Parkinson’s disease (DeNoPa) cohorts — and if you get promising results, move to a larger cohort like PPMI, which has a wealth of clinical and imaging data and biofluid samples from the same patients. We are also supporting the development of imaging tests, particularly an alpha-synuclein PET scan. This would be a game-changer for diagnosis and therapeutic development on its own. But imaging tests have also been important in validating blood-based biomarkers in Alzheimer’s and could do the same for Parkinson’s biomarker development.

Blood-based biomarkers are a huge unmet need in Parkinson’s and other neurodegenerative disorders because they are less invasive, easier to use, and lower cost than other types of biomarkers. We are building on breakthroughs in Alzheimer’s and the recent discovery of NfL as an indicator of progression to develop a biomarker framework for Parkinson’s. A comprehensive set of tests could be used in diagnosis, especially early in disease, and to predict prognosis. Imagine being able to diagnose people years before they develop Parkinson’s symptoms, or to differentiate fast progressors from slow, and identify people most at risk of developing cognitive problems. We are working toward this future in Parkinson’s research.